Expeditious synthesis of phenanthrenes via CuBr2-catalyzed coupling of terminal alkynes and N-tosylhydrazones derived from O-formyl biphenyls

Article abstract of DOI:10.1021/ol201788v

A new method for the synthesis of phenanthrenes via ligand-free CuBr2-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-formyl biphenyls has been developed. This new synthesis has wide range of functional group compatibility.

Full text of DOI:10.1021/ol201788v

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5020–5023
Expeditious Synthesis of Phenanthrenes
via CuBr2-Catalyzed Coupling of Terminal
Alkynes and N-Tosylhydrazones Derived
from O-Formyl Biphenyls
Fei Ye, Yi Shi, Lei Zhou, Qing Xiao, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
wangjb@pku.edu.cn
Received July 4, 2011
ABSTRACT
A new method for the synthesis of phenanthrenes via ligand-free CuBr2-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones
derived from o-formyl biphenyls has been developed. This new synthesis has wide range of functional group compatibility.
Phenanthrenes have attracted great attention because of
their wide presence in natural products1 as well as their
applications in medicinal chemistry2À4 and material
sciences.5 Hence, great efforts have been devoted to the
development of synthetic methodologies for phenan-
threnes. The most classical synthesis of phenanthrenes
starts from the preparation of stilbene, followed by intra-
molecular arylÀaryl bond formation.6 Another frequently
utilized strategy is to connect the two aromatic rings
through coupling reactions (in most cases by Suzu-
kiÀMiyaura cross-coupling), which is then followed by
intramolecular cyclization to construct the phenanthrene
structures.7 To construct the phenanthrene frameworks
directly, cycloisomerization of arynes with unsaturated
compounds has also been developed.8 Although great
(6) For selected reports, see: (a) Almeida, J. F.; Castedo, L.
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Fernandez, D.; Neo, A. G.; Romero, V.; Tojo, G. Org. Lett. 2003, 5,
4939–4941. (b) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R.
Tetrahedron Lett. 2002, 43, 3185–3187. (c) Wassmundt, F. W.; Kiesman,
W. F. J. Org. Chem. 1995, 60, 196–201. (d) Bremmer, M. L.; Khatri,
N. A.; Weinreb, S. M. J. Org. Chem. 1983, 48, 3661–3666.
(1) (a) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232–244.
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Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76, 509–562.
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Huffmann, C. W. J. Med. Chem. 1971, 14, 90–94.
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C. R.; Su, S.; Sydnes, M. O. Bioorg. Med. Chem. Lett. 2006, 16, 181–185.
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S. L.; Shi, Q.; Lee, K.-H. Bioorg. Med. Chem. 2006, 14, 6560–6569.
(c) Wilson, S.; Ruenitz, P. C. J. Pharm. Sci. 1993, 82, 571–574.
(4) Cannon, J. G.; Khonje, P. R.; Long, J. P. J. Med. Chem. 1975, 18,
110–112.
(7) For recent examples, see: (a) Kim, Y.-H.; Lee, H.; Kim, Y.-J.;
Kim, B.-T.; Heo, J.-N. J. Org. Chem. 2008, 73, 495–501. (b) Seganish,
W. M.; DeShong, P. Org. Lett. 2006, 8, 3951–3954. (c) Jones, S. B.; He,
L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760. (d) Monsieurs, K.;
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Rombouts, G.; Tapolcsanyi, P.; Matyus, P.; Maes, B. U. W. Synlett
2006, 3225–3230. (e) Walker, E. R.; Leung, S. Y.; Barrett, A. G. M.
Tetrahedron Lett. 2005, 46, 6537–6540. (f) Hilt, G.; Hess, W.; Schmidt,
F. Eur. J. Org. Chem. 2005, 2526–2533. (g) Iuliano, A.; Piccioli, P.;
Fabbri, D. Org. Lett. 2004, 6, 3711–3714. (h) Pathak, R.; Vandayar, K.;
van Otterlo, W. A. L.; Michael, J. P.; Fernandes, M. A.; de Koning, C. B.
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P.; Snieckus, V. Can. J. Chem. 2004, 82, 195–205. (j) Matyus, P.; Maes,
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B. U. W.; Riedl, Z.; Hajos, G.; Lemiere, G. L. F.; Tapolcsanyi, P.;
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L. Y. A.; Giro, R.; Caldas, M. J.; Atvars, T. D. Z.; Akcelrud, L. C.
Macromolecules 2006, 39, 3398–3407. (b) Liu, R.; Farinha, J. P. S.;
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r
10.1021/ol201788v
Published on Web 08/29/2011
2011 American Chemical Society

advances have been achieved in phenanthrene synthesis,
many of these methods have limitations such as the lack of
well-defined regioselectivity, low efficiency, harsh reaction
conditions, and poor accessibility of the starting substrates.9
Therefore, it is still highly desirable to develop new meth-
ods for phenanthrene synthesis.
Scheme 2. Two-Step Preparation of N-Tosylhydrazones 2aÀi
In 2006, Wang and Burton reported a method for
phenanthrene synthesis by base-promoted cyclization of
2-alkynyl-substituted biphenyls.10 The reaction is pro-
posed to involve a base-catalyzed rearrangement of the
alkyne to allene, followed by 6π cycloaddition and isomer-
ization to afford the final phenanthrene product. This
mechanism is supported by the formation of phenanthrene
from an isolated allene intermediate upon heating at high
temperature.
Recently, we have developed a novel allene synthesis by
Cu(I)-catalyzed coupling of N-tosylhydrazones with term-
inal alkynes (Scheme 1).11 Furthermore, if a suitable
intramolecular nucleophile, such as hydroxy or amino
group, is introduced to the substrate, the initially formed
allene can undergoa subsequent cyclization to affordbenz-
ofurans or indoles.12 In these reactions, Cu carbene is
generated from the in situ formed diazo substrate, which is
followed by a migratory insertion process (Ato B).Tofurther
expand this chemistry, we have conceived that if allene
intermediate D, which is similar to those reported by Wang
and Burton, is generated through Cu-catalyzed coupling of
N-tosylhydrazone and terminal alkyne, then 6π cycloaddi-
tion and isomerization should occur to afford a phenanthrene
product. In this paper, we report an efficient and straightfor-
ward phenanthrene synthesis based on this rationale.
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
base
additive
yieldb (%)
1
CuI
CuI
Cs2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOMe
K2CO3
LiOtBu
none
27
34
2
none
3
Cu(MeCN)4PF6
Cu(MeCN)4PF6
CuBr2
none
44
4c
none
52
5c
none
57
6c,d
7c,e
8c
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
CuBr2
none
19
none
7
TBAB
TBAB
TBAB
TBAB
TBAB
58
9c
66
Scheme 1. Phenanthrene Synthesis from N-Tosylhydrazone and
Terminal Alkyne
10c
11c
12c,f
CuBr2
trace
0
CuBr2
CuBr2
74
a Unless otherwise noted, reactions were carried out with 2a
(0.2 mmol), 3a (1.2 equiv), 10 mol % catalyst, and base (3.5 equiv) in
2 mL of solvent at 100 °C for 12 h. b Yield was determined by GC using
dodecane as an internal standard. c 2a to 3a ratio was 1.2:1, and the reaction
was carried out at 90 °C for 4 h and then at 120 °C for 24 h. d The reaction
was carried out in DMF. e The reaction was carried out in toluene. f 2a to 3a
ratio was 2:1.
With N-tosylhydrazone 2a and phenylacetylene 3a as
model substrates, westarted toexamine the effectiveness of
copper catalysts in phenanthrene synthesis (Table 1). To
our delight, with 10 mol % of CuI and Cs2CO3 as base, the
expected phenanthrene product 4a was formed in 27% GC
(8) (a) Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Huang, X.-C.; Li, J.-H. J. Org.
Chem. 2009, 74, 3199–3202. (b) Worlikar, S.-A.; Larock, R.-C. J. Org.
Chem. 2009, 74, 9132–9139. (c) Liu, Z.; Larock, R. C. Angew. Chem., Int.
€
Ed. 2007, 46, 2535–2538. (d) Mamane, V.; Hannen, P.; Furstner, A.
€
Chem.;Eur. J. 2004, 10, 4556–4575. (e) Furstner, A.; Mamane, V. J.
Org. Chem. 2002, 67, 6264–6267. (f) Yoshikawa, E.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2000, 39, 173–175. (g) Mandal, A. B.; Lee, G.-H.;
Liu, Y.-H.; Peng, S.-M.; Leung, M.-K. J. Org. Chem. 2000, 65, 332–336.
(h) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org. Chem.
The N-tosylhydrazones 2aÀi can be easily prepared by a
two-step transformation in good yields from o-halo-sub-
stituted benzaldehydes and aromatic boronic acids, as
outlined in Scheme 2.
~
ꢀ
ꢀ
1997, 62, 7536–7537. (i) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. J.
Am. Chem. Soc. 1999, 121, 5827–5828. (j) Dyker, G.; Kellner, A.
Tetrahedron Lett. 1994, 35, 7633–7636.
Org. Lett., Vol. 13, No. 19, 2011
5021

Figure 1. Reaction of N-tosylhydrazone 2d with various term-
inal alkynes. (a) Reaction conditions: N-tosylhydrazone 2
(0.8 mmol), 1-alkyne 3 (0.4 mmol), CuBr2 (10 mol %), LiOtBu
(1.6 mmol), TBAB (20 mol %), dioxane (4 mL), 90 °C, 4 h;
120 °C, 24 h. (b) Isolated yield by column chromatography.
Figure 2. Reaction of N-tosylhydrazone 2aÀi with terminal
alkynes. (a) Reaction conditions: N-tosylhydrazone 2 (0.8 mmol),
1-alkyne 3 (0.4 mmol), CuBr2 (10 mol %), TBAB (20 mol %),
LiOtBu (1.6 mmol), dioxane (4 mL), 90 °C, 4 h; 120 °C, 24 h.
(b) Isolated yield by column chromatography. (c) 20% yield of
alkyne was recovered. (d) The reaction was carried out at 90 °C
for 4 h and then at 120 °C for 36 h.
yield after heating the dioxane solution at 100 °C for 12 h
(entry 1). By changing the base from Cs2CO3 to LiOtBu,
the yield couldbeslightlyimproved (entry 2). The yield was
further improved by employing Cu(MeCN)4PF6 as cata-
lyst (entry 3). A significant amount of byproduct, mostly
derived from homocoupling of N-tosylhydrazone, was
observed. To minimize the homocoupling of N-tosylhy-
drazone, the reaction temperature was first set at 90 °C for
4 h. After the allene intermediate (D in Scheme 1) was
formed, the reaction temperature was raised to 120 °C in
order to facilitate the 6π cycloaddition and isomerization.
Moreover, the ratio of 2a to 3a was switched from 1:1.2 to
1.2:1. Under such conditions, the yield of 4a was improved
to 52% (entry 4). CuBr2 was also found to be effective to
give 4a in comparable yield (entry 5). Two solvents, DMF
and toluene, were investigated, but both were found to be
ineffective for the reaction (entries 6 and 7). Next, the effect
of additive was investigated, and TBAB (tetrabuty-
lammonium bromide) was found to facilitate the reaction
(entries 8 and 9). Finally, with CuBr2 as catalyst two
commonly used bases, NaOMe and K2CO3, were exam-
ined, and both were found ineffective for the reaction
(entries 10 and 11). On the basis of the above experiments,
the optimized reaction conditions are summarized as
follows: 2a/3a = 2:1, CuBr2 (10 mol %), TBAB, dioxane,
90 °C for 4 h and then 120 °C for 24 h (entry 12).
(9) For other selected reports on the synthesis of phenanthrene, see:
(a) Jung, M. E.; Hagiwara, A. Tetrahedron Lett. 1991, 32, 3025–3028. (b)
Merlic, C. A.; Roberts, W. M. Tetrahedron Lett. 1993, 34, 7379–7382. (c)
Paolobelli, A. B.; Ruzziconi, R.; Lupattelli, P.; Scafato, P.; Spezzacatena,
C. J. Org. Chem. 1999, 64, 3364–3368. (d) Catellani, M.; Motti, E.;
Baratta, S. Org. Lett. 2001, 3, 3611–3614. (e) Zhang, Y.; Herndon, J. W.
Org. Lett. 2003, 5, 2043–2045. (f) Shen, H.-C.; Tang, J.-M.; Chang,
H.-K.; Yang, C.-W.; Liu, R.-S. J. Org. Chem. 2005, 70, 10113–10116. (g)
With the optimized reaction conditions in hand, we
next investigated the scope of the reaction with a series of
N-tosylhydrazones 2aÀi and terminal alkynes. The results
are summarized in Figures 1 and 2, respectively.
As shown in Figure 1, the reaction was found to be not
significantly affected by the substituents on the aromatic
ring of the terminal alkynes. Aryl-substituted alkynes with
both electron-donating and electron-withdrawing groups,
such as methoxyl, alkyl, halogen, and trifluoromethyl,
could be smoothly transformed into the corresponding
phenanthrene products.
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6814–6816.
(10) Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 5295–5298.
(11) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2011, 50, 1114–1117.
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Lett. 2011, 13, 968–971.
5022
Org. Lett., Vol. 13, No. 19, 2011

Next, we studied the scope of N-tosylhydrazone. Various
substituted N-tosylhydrazones were employed as substrates
to react with aryl terminal alkynes (Figure 2). In all cases,
the reaction proceeded smoothly to afford the correspond-
ing phenanthrenes in moderate to good yields. It is note-
worthy that the N-tosylhydrazones containing heterocycles,
such as pyridine and thiophene, can also undergo a cycliza-
tion process with the allene moiety to afford the correspond-
ing phenanthrene products (4j,nÀp). To our delight, the free
hydroxyl group could tolerate the reaction condition to
afford the phenanthrene product in comparable yield (4l).
In conclusion, we have developed a new method for
the synthesis of phenanthrene derivatives, which em-
ploys easily accessible N-tosylhydrazones derived from
O-formyl biphenyls and terminal alkynes as substrates
and CuBr2 as catalyst. The reaction involves a sequence
of CuBr2-catalyzed coupling/allenylation/6π electron
cycloaddition/aromatization. The advantages of this new
method involve the easy preparation of the N-tosylhydra-
zone derivatives and the use of inexpensive CuBr2 as
catalyst without use of ligand. Further investigation of
this method is ongoing in our laboratory, and the results
will be reported in due course.
Acknowledgment. Financial support from 973 Program
(No. 2009CB825300), National Natural Science Founda-
tion of China (Grant No. 20902005, 20832002, 20772003,
20821062), GSK R&D China, and China Postdoctoral
Science Foundation is gratefully acknowledged.
Supporting Information Available. Procedures for synth-
esis and characterization of products (1Hand13CNMRdata).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5023